Certain heterocyclic isothiocyanates used as fungicides

ABSTRACT

FUNGICIDAL COMPOSITIONS OF AND METHODS OF COMBATTING FUNGI USING, CERTAIN HETEROCYCLIC ALKYLTHIOCYANATES AND ISOTHIOCYANATES, I.E., FURFURYL, DIHYDRO AND TETRAHYDRO FURFURLY, THENYL, CHLOROTHENYL, DIHYDROPYRANYL, AND PICOLYL THIOCYANATES AND ISOTHIOCYANATES, SOME OF WHICH ARE KNOWN, AND WHICH MAY BE PRODUCED BY CONVENTIONAL MEANS.

United States Patent Ofice Patented June 19, 1973 3,740,435 CERTAIN HETEROCYCLIC ISOTHIOCYANATES USED AS FUNGICIDES Peter E. Newallis, Leawood, Kans., Albert J. Poje, Grandview, Mo., and Peter F. Epstein, Prairie Village, Kans., assignors to Chemagro Corporation, Kansas City, M0. N Drawing. Filed Nov. 20, 1970, Ser. No. 91,543 Int. Cl. A01n 9/18, 9/28 US. Cl. 424-285 Claims ABSTRACT OF THE DISCLOSURE Fungicidal compositions of and methods of combatting fungi using, certain heterocyclic alkylthiocyanates and isothiocyanates, i.e., furfuryl, dihydro and tetrahydro furfuryl, thenyl, chlorothenyl, dihydropyranyl, and picolyl thiocyanates and isothiocyanates, some of which are known, and which may be produced by conventional means.

The present invention relates to and has for its objects the use as fungicides of certain heterocyclic alkylthiocyanates and isothiocyanates, some of which are known as nematicides, in the form of mixtures of such compounds with solid dispersible carrier vehicles or with liquid dispersible carrier vehicles containing a surface-active agent, and methods for using such compounds in a new way especially for combatting fungi, with other and further objects becoming apparent from a study of the within specifications.

It is already known that some heterocyclic alkyl isothiocyanates can be used for the control of parasitic worms such as nematodes (US. Pat. 2,946,720) and as flavoring agents for foods and beverages (-U.S. Pat. 2,905,701). Other reports describing heterocyclic alkyl isothiocyanates can be found in: J. Am. Chem. Soc., 51, 3131 (1920); Bull. Chem. Soc. Japan, 33, 1465 (1960); Ann, 445, 201 (1925); Bull. Chem. Soc. Japan, 36, 108 (1963).

It has now been found in accordance with the present invention that certain heterocyclic alkyl thiocyanatesand isothiocyanates, i.e., furfuryl, tetrahydrofurfuryl, picolyl, thenyl and chlorothenyl thiocyanates and isothiocyanates possess valuable fungicidal properties.

It has been found inaccordance with the present invention that certain heterocyclic alkyl thiocyanates and isothiocyanates, some of which are known, havin the formulae:

wherein:

R and R are each individually hydrogen or alkyl and Z is furyl, dihydrofuryl, tetrahydrofuryl, benzofuryl, pyranyl, dihydropyranyl, tetrahydropyran-yl, thienyl, pyridyl, pyrrolyl, picolyl, indolyl, dihydrothienyl1 oxide, dihydrothienyl-l, l-dioxide or tetrahydrothienyll-dioxide as well as alkyl, chloro, bromo and nitro substitution products thereof, alkyl in all substances containing from 1 to 6 carbon atoms,

have strong fungicidal properties.

Surprisingly, some of the heterocyclic alkyl isothiocyanates of the instant invention exhibit a high degree of soil fungicidal activity and are effective against a broad spectrum of fungi. The active compounds of this invention therefore represent an enrichment of the art.

It is very surprising that the heterocyclic alkyl thiocyanates and isothiocyanates which are usable according to the present invention have such a high degree of fungicidal activity at rates substantially below those reported for nematicidal effectiveness. The fungicidal compositions and methods of combatting fungi using such active compounds according to the present invention therefore also represent a valuable enrichment of the art.

In the Formulae I and II, R and R preferably represent alkyl radicals having 1 to 4 carbons or hydrogen or any combination thereof and the thienyl radical can be substituted by one or more halogen atoms such as chlorine or bromine: fungicides of Formula I are preferred.

As examples of heterocyclic alkyl thiocyanates and isothiocyanates which can be used according to the instant invention, the following compounds may be cited in particular:

(1 Z-furfuryl isothiocyanate (10) S-methyl furfuryl isothiocyanate (20) S-chlorofurfuryl isothiocyanate (6) 2-thenyl isothiocyanate (7) 5-chloro-2-thenyl isothiocyanate (8) '5-bromo-2-thenyl isothiocyanate 1 1 S-methyl-Z-thenyl isothiocyanate l2) 2- (2-furyl)-ethyl isothiocyanate (l3) 1-(2-furyl)-ethyl isothiocyanate (4) 2-pyridylmethyl isothiocyanate (14) 2-benzofurfuryl isothiocyanate (2) tetrahydro-Z-furfuryl isothiocyanate 15 l-methyl-Z-pyrrolemethyl isothiocyanate (16) 1-methyl-2-indolemethyl isothiocyanate (3) 2-isothiocyanato-3,4-dihydro-2H-pyran (17) 3-isothiocyanatomethyl 2,5-dihydrothiophene-l,1-

dioxide (18) Tetrahydro-Z-pyranyl isothiocyanate (l9) 6-methyl-2-picoly1 isothiocyanate (21) 5-nitro-2-furfuryl isothiocyanate (22) Z-tetrahydrofurfuryl thiocyanate (23) 2,5-dibromo-3-thenyl thiocyanate (24) 2,5-dichloro-3-thenyl thiocyanate (25) 2,5-dichloro-3-thenyl isothiocyanate Some of the substances according to the present invention are new, although they can be manufactured simply by known methods. The compounds of this invention are obtained, for example, whenever the appropriate hetero cyclic alkyl amine is reacted with carbon disulfide and a chloroformate substantially between about -30 to +50 C. but preferably between 10 to +30 C. in the presence of a base selected from the group of inorganic bases such as sodium or potassium hydroxide or organic tertiary amines such as pyridine or triethylamine. With organic bases, it is optionally preferred to use inert solvents such as chloroform or dioxane.

Alternatively, some of the new and old compounds can be prepared by the isomerization of the corresponding thiocyanate, by heating optionally in an inert solvent at substantially between about +30 C. to C., preferably a dipolar aprotic solvent such as dimethyl formamide, sulfolane, acetonitrile and the like.

Advantageously, the active compounds according to the present invention, exhibit strong fungitoxic properties, with comparatively low toxicity to warm-blooded creatures and concomitantly low phytotoxicity. Hence, the instant compounds are suitable for use as plant protection agents and, in the hygiene field, for the control of fungi, particularly phytopathogenic fungi.

As to the fungicidal properties, the instant compounds possess a broad spectrum of activity.

Thus, the instant compounds can "be used for the control of fungi from the most widely different classes of fungi, such as for example: Archimycetes, Phycomycetes, Ascomycetes, Basidiomycetes, Fungi imperfecri, and the like.

The instant compounds can give particularly effective results against parasitic fungi on aboveground parts of plants, fungi causing tracheomycosis, which attack the plant from the soil, seed-borne fungi, and soil-borne fungi, such as the organisms Caratocystis ulmi, Colletotrichum obiculare, F usarium Iycopersici, F usarium nivale, H elminthosparium satirum, Rhizoctonia solani, Verticillium alboatrum, Pytlzizmz, Alrernaria ustilago, and the like.

The active compounds according to the instant invention can be utilized, if desired, in the form of the usual formulations or compositions with diluents or extenders, i.e., dispersible carrier vehicles, such as solutions, emulsions, suspensions, emulsifiable concentrates, spray powders, pastes, soluble powders, dusting agents, granulates, etc. These are prepared in known manner, for instance by extending the active compounds with dispersible liquid diluent carriers and/or dispersible solid carriers optionally with the use of carrier vehicle assistants, e.g., surfaceactive agents, including emulsifying agents and/or dispersing agents, whereby, for example, in the case where water is used as diluent, organic solvents may be added as auxiliary solvents (cf. Agricultural Chemicals, March 1960, pp. 35-38). The following may be chiefly considered for use as carrier vehicles for this purpose: dispersible liquid diluent carriers, such as aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated, especially chlorinated, aromatic hydrocarbons (e.g. chlorobenzenes, etc.), parafi'ins (e.g. petroleum fractions), chlorinated aliphatic hydrocarbons (e.g. methylene chloride, etc.), alcohols (e.g. methanol, ethanol, propanol, butanol, etc.) amines (e.g. ethanolamine, etc.) ethers, etheralcohols (eg. glycol monomethyl ether, etc.), amides (e.g. dimethyl formamide, etc.), sulfoxides (e.g. dimethyl sulfoxide, etc.) ketones (e.g. acetone, etc.), and water; as well as dispersible finely divided solid carriers, such as ground natural minerals (e.g. kaolins, alumina, silica, chalk, i.e. calcium carbonate, talc, kieselguhr, etc.) and ground synthetic minerals (e.g. highly dispersed silicic acid, silicates, e.g. alkali silicates, etc.); whereas the following may be chiefly considered for use as carrier vehicle assistants, e.g. surface-active agents, for this purpose: emulsifying agents, such as nonionic and anionic emulsifying agents (e.g. polyethylene oxide esters of fatty acids, polyethylene oxide ethers of fatty alcohols, alkyl sulfonates, aryl sulfonates, etc., and especially alkyl aryl-poly glycol ethers, magnesium stearate, sodium oleate, etc.); and dispersing agents, such as lignin, sulfite waste liquors, methyl cellulose, etc.

Such active compounds may be employed alone or in the form of mixtures with one another and/or with other known compatible active agents, especially plant protection agents, such as other fungicides, insecticides, bactericides, etc., if desired, or in the form of particular dosage preparations for specific application made therefrom, such as solutions, emulsions, suspensions, powders, pastes, granulates and aerosols which are thus ready for use.

As concerns comercially marketed preparations, these generally contemplate carrier composition mixtures in which the active compound is present in an amount substantially between about O.1%, by Weight of the mixture, whereas carrier composition mixtures suitable for direct application or field application generally contemplate those in which the active compound is present in an amount substantially between about (MM-2.0%, preferably 0.01-0.-8%, by weight of the mixture. Thus, the present invention contemplates overall compositions which comprise mixtures of a dispersible carrier vehicle such as (l) a dispersible carrier solid, or (2) a dispersible carrier liquid preferably including a carrier vehicle assistant, e.g. surface-active agent, and an amount of the active compound which is effective for the purpose in question and which is generally between about 0:0 l95%, by weight of the mixture.

Furthermore, the present invention contemplates methods of selectively controlling or combatting fungi, which comprises applying to at least one of (a) such fungi and (b) their habitat, i.e., the locus to be protected, a fungicidally effective amount of the particular active compound of the invention alone or together with a carrier vehicle as noted above. The instant formulations or compositions are applied in the usual manner, for instance by spraying, atomizing, vaporizing, scattering, dusting, watering, sprinkling, pouring, and the like.

It will be realized, of course, that the concentration of the particular active compound utilized in admixture with the carrier vehicle will depend upon the intended application. Therefore, in special cases, it is possible to go above or below the aforementioned concentration ranges.

The following examples illustrate without limitation, the fungicidal activity of the particular active compounds of the present invention.

EXAMPLE 1.*FUNGICIDAL ACTIVITY Agar plate fungicide test (Mycelium growth) Solvent: 99 parts by weight distilled water Dispersing agent: 1 part by weight To produce a suitable preparation of the particular active compound, 1 part by weight of such active compound is mixed With the stated amount of solvent containing the stated amount of dispersing agent.

The active compound preparation is added to potato dextrose agar (which has been liquefied by heating) in such an amount that the desired concentration of active compound is provided therein. After thorough shaking to achieve a uniform dispersion of the active compound, the agar is poured into Petri dishes under sterile conditions. Control dishes to which the active compound preparation has not been added are also set up.

When the mixture of substrate and active compound has solidified, the dishes are inoculated in the center of the plate with the species of fungi stated in the table and incubated at room temperature (21-25 C.) for 7 days.

After this time, the extent of mycelial growth is determined in relation to the growth of the untreated conrol by computing the area of the fungal colony, based on measuring the average radius from the central point of inoculation to the periphery of mycelial growth. The inhibtion of fungal growth is expressed by the values 0 to 10, wherein 0 means that there is no inhibition (full growth as in control) and 10 means that there is complete inhibition (absence of growth).

The particular active compounds tested, their concentrations in the agar used, the test fungi and the inhibition effects achieved can be seen from the following Table I.

TABLE 1.AGAR PLATE TEST DATA Colleto- Fusarz'um Helmi'ntho- Rate Ceratocystis trichum 07:11.; I. Fusarium sporium Rhizactoma Verticillum Active compound (p.p.m.) ul'mi obiculare lycopersici 'm'vale sativum solani alboratrum (1) 500 10 10 10 10 10 10 10 100 10 10 10 10 10 10 10 10 10 10 10 10 1O 10 10 OHzNCS O (2) 500 10 10 10 10 10 10 10 100 10 10 10 10 10 1O 10 10 10 10 3.6 10 10 10 10 OHZNCS 3 500 10 10 10 10 10 1O 10 A 100 10 10 10 10 10 10 10 10 10 10 10 1O 10 1O 10 O CH2NCS 4 500 10 10 10 10 10 10 10 CHzNCS 100 10 10 10 10 10 10 10 10 10 10 3. 6 9. 6 10 7. 5 7. 5

\ CHzCH;NCS

(6) 10 7. 5 10 10 1O 10 10 7. 5 10 9. 6 10 7. 5 10 0 10 0 10 0 CH2NCS S (7) 10 0 0 7.5 10 13 7. 5 0 0 3. 6 0 7. 5 7. 5 0 0 0 0 0 Cl- CHrNCS s 10 0 7. 5 7. s 10 7. 5 3. 6 0 7. 5 7. 5 7. 5 7. 5 0 0 0 0 0 0 Br- CI{2NCS (9) 10 0 0 3'. 6 10 10 CH(CH3)2 7.5 0 0 3.6 0 0 0 0 0 0 0 0 HNCS O (22) 10 7. 5 7. 5 10 0 0 7. 5 0 0 0 0 0 7. 5 0 0 0 0 0 CH2SCN 0 (23) CH2SCN 10 10 10 10 10 10 0 0 0 7. 5 0 0 0 0 0 0 0 0 Br Br S (24) CHzSCN 10 7. 5 7. 5 0 0 0 0 0 O 0 0 0 :0 0 0 0 0 0 0 Cl- 8 l 25 CHgNCS o 10 1o 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 01- S Cl EXAMPLE 2.-FUNGICIDAL ACTIVITY Soil fungicide test (rolled towel) Wettable powder base consisting of:

Parts by weight Hydrated silica 92 Sodium lignin sulfonate 4 Polycondensate of ethylene oxide, propylene oxide and propylene glycol (mol. wt. about 1000) 4 parts by weight of clay (attapulgite) and 500 parts by weight of soil infected with the damping oif organism (pythium), to provide 2 corresponding soil portions.

After standing at room temperature for 24 hours, each said active compound-containing soil portion is divided up into three batches and 50 pea seeds are added to each batch. Each batch is then rolled in a paper towel and incubated in a separte can covered with a plastic sheet for 5 days at 4.4 C. and then for an additional 4 days at 24 C.

At the end of the 9 days, the degree of effectiveness in preventing fungal damage of the pea seeds is determined and expressed by the values 0 to 10, wherein 0 means that there is no control of damage, i.e. as much as with no active compound, and 10 means that there is control, i.e. no damage.

TABLE 2.-SOIL FUNGICIDAL TEST DATA In the corresponding manner there are obtained:

Disease control indices n p.p.m.

Active compound 100 50 25 12 6 -CH2NGS O CHzNCS CH2NCS O CHzNCS N -CH2CH2NCS s OH2NCS (31- s CH2NCS (8)-": 2 0 uni-n":

Brs CH2NCS The following further examples and table of compounds illustrate, without limitation, a number of heterocyclic alkyl isothiocyanates usable in accordance with the present invention.

EXAMPLE 3 l J-JJH NCS A mixture of 50 g. (0.515 mole) of furfuryl amine and 50 g. (0.5 mole) triethyl amine was dissolved in 70 ml. of dioxane and cooled to -10 C. To this mixture was added 40 g. (0.525 mole) of carbon disulfide and the reaction mixture was allowed to warm to room temperature. Ethyl chloroformate, 57 g. (0.53 mole) was added dropwise followed by the addition of 200 ml. of chloroform and an additional 50 g. (0.5 mole) of triethyl amine. The reaction mixture was stirred at room temperature for 60 hours, the solid was filtered and the organic solution was washed with water. After evaporation of the solvent, the residue was dried by azeotroping with benzene. Distillation gave 19 g. of Z-furfuryl isothiocyanate as a colorless liquid B.P. 5254 C. (0.9 mm.).

Calc. (percent): C, 51.8; H, 4.3; N, 10.1. Found (percent): C, 51.8; H, 3.9; N, 10.0.

Compound Physical properties (2) 61 C. (0.5 mm.)

o -CHzNCS (3)- ..:.t.: 63 C. (0.3 mm!) -CH2NCS \O/ (4)- 112 C. 125 mm.) --CHzNOS (5)- .::.r 93 C. (0.45 min.)

N -OHzCH2NGS EXAMPLE 4 A mixture of 12.8 grams (0.08 mole) of 2-thenyl thiocyanate, 25 ml. of dimethyl formamide and 0.5 gram of zinc chloride were heated at C. for three hours. The reaction mixture was cooled, poured into water and the organic layer was extracted three times with a 1:1 (v./v.) mixture of benzene and heptane. The combined extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was distilled giving 6.1 grams (48% yield) of 2-thenyl isothiocyanate boiling at 65 C. (0.06 mm).

In the corresponding manner, there are obtained:

To a solution of 27 g. (0.193 mole) of isopropyl 2- furyl carbinol in 80 ml. of pyridine was added with cool ing 22 g. (0.193 mole) of methane sulfonyl chloride over a one hour period. After standing overnight the solid mass was dried in an oven at 50 C. and dissolved in 600 mls. of acetone. To this solution was added 30 g. (0.3 mole) of potassium thiocyanate and the reaction mixture was refluxed for 3 hours. After lfiltration and removal of the solvent by evaporation, the resultant oil was extracted with 500 ml. of methylene chloride, washed with Water, dried over anhydrous magnesium sulfate and filtered. Removal of the solvent by evaporation left 30 g. of residual oil which was twice distilled to give 6 g. (17% yield) of a-isopropyl-Z-furfuryl isothiocyanate as a pale yellow liquid, B.P. 48 C. (0.07 mm).

It will be realized by the artisan that all of the foregoing compounds contemplated by the present invention possess the desired strong fungicidal properties, with regard to a broad spectrum of activity, as well as comparatively low phytotoxicity, enabling such compounds to be used for effective control and/ or elimination of fungi by the application of such compounds to such fungi and/ or their habitat.

It will be appreciated that the instant specification and examples are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention which is to be limited only by the scope of the appended claims.

What is claimed is:

1. A method of combatting fungi which comprises applying to said fungi, a fungicidally effective amount of a compound of the formula:

wherein R and R are each individually hydrogen or alkyl of 1 to 6 carbon atoms and Z is furyl, dihydrofuryl, tetrahydrofuryl, benzofuryl, pyranyl, dihydropyranyl or tetrahydropyranyl which may be unsubstituted or substituted with alkyl of 1 to 6 carbon atoms, chloro, bromo or nitro.

2. The method of claim 1, wherein the compound is Z-furfuryl isothiocyanate of the formula:

k LCHrNCS 3. The method of claim 1, wherein the compound is S-methyl furfuryl isothiocyanate of the formula:

5 CHr-LOLCILNOS 4. The method of claim 1, wherein the compound is S-chlorofurfuryl isothiocyanate of the formula:

Cll LCH2NCS 5. The method of claim 1, wherein the compound is r Z-(Z-furyD-ethyl isothiocyanate of the formula:

OTHER REFERENCES Chemical Abstracts, 54:3838i-3839a (1960).

ALBERT T. MEYERS, Primary Examiner 30 L. SCHENKMAN, Assistant Examiner US. Cl. X.R. 

